Mandal Sumit Kumar, Muzaffar-Ur-Rehman Mohammed, Puri Sonakshi, Sharma Pankaj Kumar, Murugesan Sankaranarayanan, Deepa P R
Biochemistry and Enzyme Biotechnology Laboratory, Department of Biological Sciences, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India.
Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani, Rajasthan, 333 031, India.
Sci Rep. 2025 Jul 24;15(1):26995. doi: 10.1038/s41598-025-12357-0.
Polydatin (PD), a stilbenoid resveratrol-derivative in Vitaceae, Liliaceae, and Leguminosae, exhibits pharmacological protection in metabolic disorders. This study investigated Polydatin, as a potential pan-PPAR agonist for treating non-alcoholic fatty liver disease (NAFLD). High-throughput-virtual-screening (HTVS) was performed to identify potential pan-PPAR agonists, followed by in vitro testing of Polydatin in HepG2 steatosis model. Effects on lipid metabolism and oxidative stress, PPAR signaling gene expression analysis, and GC-MS profiling were compared with the hepatoprotectant Silymarin. Pan-PPAR targeted HTVS of PhytoHub natural products database, followed by molecular docking/dynamics simulations, revealed lead-candidate, Polydatin, which was tested in steatotic cells for gene and protein deregulations by qRT-PCR and western blot, followed by GC-MS analysis of biochemical metabolites. HTVS revealed 53 potential pan-PPAR agonists. Molecular docking and dynamics simulations suggested that PD, a stable ligand for PPARs (α,β/δ,γ), exhibited strong binding. Polydatin treatment decreased ALT, triglycerides, and oxidative stress, wherein ROS and malondialdehyde levels decreased by 60.94% and 28%, respectively. PD upregulated PPARs, AMPK, GLUT2, and CPT1α, while downregulating lipogenic enzymes (ACC1, FASN, SCD1). GC-MS analysis revealed Polydatin mediated impact on saturated FFAs-palmitic acid, stearic acid, and unsaturated fatty acid product of SCD1, oleic acid. HTVS identified PD as a promising pan-PPAR agonist, which favorably ameliorated changes in lipid, glucose, and overall energy metabolism in steatotic NAFLD, by modulating PPAR(α,β/δ,γ) expressions and associated downstream lipogenic and lipid-utilization mechanisms, supporting anti-steatotic efficacy of Polydatin.
白藜芦醇苷（PD）是葡萄科、百合科和豆科中的一种芪类白藜芦醇衍生物，在代谢紊乱中具有药理保护作用。本研究调查了白藜芦醇苷作为治疗非酒精性脂肪性肝病（NAFLD）的潜在泛过氧化物酶体增殖物激活受体（PPAR）激动剂的情况。进行了高通量虚拟筛选（HTVS）以鉴定潜在的泛PPAR激动剂，随后在HepG2脂肪变性模型中对白藜芦醇苷进行体外测试。将其对脂质代谢和氧化应激的影响、PPAR信号基因表达分析以及气相色谱-质谱联用（GC-MS）分析结果与保肝药物水飞蓟宾进行了比较。对植物源天然产物数据库进行泛PPAR靶向的HTVS，随后进行分子对接/动力学模拟，发现了候选先导化合物白藜芦醇苷，并通过实时定量聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法（western blot）在脂肪变性细胞中对其基因和蛋白质失调情况进行了检测，随后通过GC-MS分析生化代谢产物。HTVS揭示了53种潜在的泛PPAR激动剂。分子对接和动力学模拟表明，白藜芦醇苷是PPARs（α、β/δ、γ）的稳定配体，具有很强的结合能力。白藜芦醇苷治疗降低了谷丙转氨酶（ALT）、甘油三酯水平以及氧化应激，其中活性氧（ROS）和丙二醛水平分别降低了60.94%和28%。白藜芦醇苷上调了PPARs、腺苷酸活化蛋白激酶（AMPK）、葡萄糖转运蛋白2（GLUT2）和肉碱棕榈酰转移酶1α（CPT1α），同时下调了生脂酶（乙酰辅酶A羧化酶1（ACC1）、脂肪酸合酶（FASN）、硬脂酰辅酶A去饱和酶1（SCD1））。GC-MS分析显示，白藜芦醇苷对饱和脂肪酸（棕榈酸、硬脂酸）以及SCD1的不饱和脂肪酸产物油酸产生了影响。HTVS确定白藜芦醇苷是一种有前景的泛PPAR激动剂，它通过调节PPAR（α、β/δ、γ）的表达以及相关的下游生脂和脂质利用机制，有利地改善了脂肪变性非酒精性脂肪性肝病中脂质、葡萄糖和整体能量代谢的变化，支持了白藜芦醇苷的抗脂肪变性功效。
